The Pacific Northwest (PNW) Prostate Cancer SPORE continuation grant represents a coordinated effort of four institutions with established programs and strengths in translational prostate cancer research and career development: 1) the Fred Hutchinson Cancer Research Center (FHCRC); 2) the University of Washington (UW) and its affiliated institutions; 3) the University of British Columbia and the Prostate Centre of Vancouver General Hospital (UBC); and, 4) Oregon Health and Sciences University (OHSU). These Seattle-, British Columbia- and Portland-based institutions have large multidisciplinary teams of investigators and laboratories dedicated to prostate cancer research and a history of working closely together within this larger milieu. The respective teams of clinicians and researchers at these institutions bring considerable scientific depth and breadth required for confronting the most challenging problems blocking progress in our ultimate goal of reducing the morbidity and mortality associated with prostate cancer. This SPORE proposal provides the blueprint for building a large coordinated translational prostate cancer effort spanning the PNW. All participating institutions have made substantial commitments toward supporting the SPORE and its innovative, translational projects: 1) A population-based cohort study to identify metastasis-modifier alleles predictive of prostate cancer progression and mortality; 2) A clinical study of prostate cancer radiation resistance and associated cellular mechanisms responsible for treatment failure; 3) A translational study of the role of Hsp27 inhibition to target hormone refractory prostate cancer and mechanisms of cellular response to stress; 4) A neoadjuvant study to confirm preclinical data showing that combined inhibition of androgens and the IGF receptor enhance prostate cancer response; and, 5) A study of tumor response to complete androgen ablation in relation to tissue levels of androgens and AR activity. We also propose four Cores to support these projects: 1) leadership and administration; 2) tissue/specimens; 3) biostatistics; and 4) clinical research. In addition, we propose a Career Development Program and a Developmental Research Program that will significantly embellish and strengthen the translational goals of our prostate cancer research program and expand opportunities for engaging young as well as established investigators in our multidisciplinary environment.